Cold atmospheric plasma differentially affects cell renewal and differentiation of stem cells and APC-deficient-derived tumor cells in intestinal organoids

Alia Hadefi,François Reniers,Marie-Isabelle Garcia,Frédérick Libert,Morgane Leprovots,Orianne Bastin,Max Thulliez,Anne Lefort,Alain Delchambre,Jacques Devière,Antoine Nonclercq

doi:10.1038/s41420-022-00835-7

Alia Hadefi, François Reniers + Show 9 more

Open Access

https://doi.org/10.1038/s41420-022-00835-7

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Abstract

Cold atmospheric plasma (CAP) treatment has been proposed as a potentially innovative therapeutic tool in the biomedical field, notably for cancer due to its proposed toxic selectivity on cancer cells versus healthy cells. In the present study, we addressed the relevance of three-dimensional organoid technology to investigate the biological effects of CAP on normal epithelial stem cells and tumor cells isolated from mouse small intestine. CAP treatment exerted dose-dependent cytotoxicity on normal organoids and induced major transcriptomic changes associated with the global response to oxidative stress, fetal-like regeneration reprogramming, and apoptosis-mediated cell death. Moreover, we explored the potential selectivity of CAP on tumor-like Apc-deficient versus normal organoids in the same genetic background. Unexpectedly, tumor organoids exhibited higher resistance to CAP treatment, correlating with higher antioxidant activity at baseline as compared to normal organoids. This pilot study suggests that the ex vivo culture system could be a relevant alternative model to further investigate translational medical applications of CAP technology.

Highlights

Cold atmospheric plasma (CAP) is a partially or totally ionized gas including photons, electromagnetic fields, electrons, ions, and neutral radicals such as reactive oxygen and nitrogen species (RONS) [1]
Under the 80 W-dose condition, dark declining structures were observed, accompanied by overall reduced survival rate tendency as compared to controls [34.2 ± 1.6% in CAP 60 s/80 W versus 44.5 ± 4.3% in untreated samples, respectively, unpaired t-test P = 0.0698]. These experiments indicate that direct CAP treatment alters the growth capacity of healthy intestinal stem cells (ISCs) in a dosedependent manner
The present study demonstrated the relevance of a 3D organoid culture to investigate the biological effects of CAP on normal epithelial stem cells and tumor cells isolated from the mouse small intestine, and unexpectedly showed higher resistance of tumor organoids to CAP treatment

Summary

Introduction

Cold atmospheric plasma (CAP) is a partially or totally ionized gas including photons, electromagnetic fields, electrons, ions, and neutral radicals such as reactive oxygen and nitrogen species (RONS) [1]. This innovative technology has generated growing interest for various applications in the biomedical field such as blood coagulation, sterilization, wound healing and anti-cancer therapy [2]. Number of studies have reported that CAP exerts cytotoxic effects when applied directly to cultured cells or indirectly through a plasmaactivated medium (PAM), as well as anti-tumoral activity [3, 4]. The cytotoxic effects are mainly attributed to the production of short and long-lived RONS that generate a redox imbalance, leading to increased intracellular oxidative stress along with the damage of cellular components, such as proteins, lipids, and DNA [5, 6]. Active cancer cells are reported to exhibit a higher basal level of oxidative stress as compared to healthy cells, which could explain the reported selectivity of the anti-tumoral effects of CAP [7, 8]. The impact of CAP treatment on healthy tissues that naturally have a high renewal rate has not been fully investigated

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